1. Field of the Invention
This invention relates to a novel and improved method for synthesizing leukotriene B.sub.4 and derivatives thereof, and to novel intermediates useful in said process.
2. The Prior Art
Leukotriene B.sub.4 (hereinafter "LTB4", illustrated as Compound 1 in FIG. 1) is an important metabolite of the 5-lipoxygenase arachidonic acid peroxidation pathway recently isolated by incubation with polymorphonuclear leukocytes. Borgeat, P; Samuelsson, B., J. Biol. Chem., 254, 2643 (1979). Implicated as a mediator in inflammation, this biomolecule exhibits potent chemotactic properties, facilitates adhesion of neutrophils to the endothelium, causes degranulation and release of lysosomal enzymes, increases the intracellular levels of calcium ions, and induces vascular permeability. Smith, M. J. H., Gen. Pharmacol., 12, 211 (1981); Ford Hutchinson, A. W., J. R. Soc. Med., 75, 831 (1981); Borgeat, P., Sirois, P., J. Med. Chem., 24, 121 (1981); Samuelsson, B., Science (Washington, D.C.), 220, 568 1983); Piper, P. J., Trends Pharmacol. Sci., 1983, 4, 75. The major use for LBT4 is as a research tool for stimulating certain physical states. For example, it can be used for stimulating inflammation for testing antiinflammatory compounds.
Due to its physiological importance and its low natural abundance, several syntheses of LTB4 have already appeared. Corey, E. J., Marfat, A., Goto, G., Brion, F., J. Am Chem. Soc., 102, 7984 (1980); Corey, E. J., Marfat, A., Munroe, J., Kim, K. S., Hopkins, P. B., Brion, F., Tetrahedron Lett., 22, 1077 (1981); Guindon, Y., Zamboni, R., Lau, C.-K., Rokach, J., Tetrahedron Lett., 23, 739, 2631 (1982); Mills, L. S., North, P. C., Tetrahedron Lett., 24, 409 (1983). One of the more successful synthesis methods known in the art is that disclosed in Nicolau, K. C., Zipkin, R. D., Dolle, R. E. and Harris, B. D., "A General and Stereocontrolled Total Synthesis of Leukotriene B.sub.4 and Analogues," J. Am. Chem. Soc., 106, 3548 (1984). This process is illustrated in the chemical flow chart shown in FIG. 2. Aldehyde 9 is coupled with the anion of phosphonate 6 to afford product 10. Pure 10, obtained after chromatographic separation, is then subjected to controlled hydrogenation (Lindlar catalyst, CH.sub.2 Cl.sub.2) to afford a mixture of tetraene 8, monoacetylene 11, and recovered starting material. Finally, removal of all three protecting groups from 8 with excess n-Bu.sub.4 NF leads to LTB4 1. While this process represents an improvement over many of the previously known processes for preparing LTB4, there is still a need for a process which will provide LTB4 in fewer steps and greater yields.
It is therefore an object of this invention to provide a process which can be used to prepare LTB4 and useful analogues thereof. It is another object of this invention to provide novel intermediate compounds which can be used in the preparation of LBT4 and useful analogues thereof.